Dewick P.M. Medicinal natural products VCH-Wiley, Weinheim, 2002 / booktext@id88013692placeboie

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Belladonna herb typically contains 0.3–0.6% of alkaloids, mainly (−)-hyoscyamine (Figure 6.4). Belladonna root has only slightly higher alkaloid content at 0.4–0.8%, again mainly (−)-hyoscyamine. Minor alkaloids including (−)-hyoscine (Figure 6.4) and cuscohygrine (Figure 6.3) are also found in the root, though these are not usually significant in the leaf. The mixed alkaloid extract from belladonna herb is still used as a gastrointestinal sedative, usually in combination with antacids. Root preparations can be used for external pain relief, e.g. in belladonna plasters.

Stramonium

Datura stramonium (Solanaceae) is commonly referred to as thornapple on account of its spikey fruit. It is a tall bushy annual plant widely distributed in Europe and North America, and because of its alkaloid content is potentially very toxic. Indeed, a further common name, Jimson or Jamestown weed, originates from the poisoning of early settlers near Jamestown, Virginia. At subtoxic levels, the alkaloids can provide mild sedative action and a feeling of well-being. In the Middle Ages, stramonium was employed to drug victims prior to robbing them. During this event, the victim appeared normal and was cooperative, though afterwards could usually not remember what had happened. For drug use, the plant is cultivated in Europe and South America. The leaves and tops are harvested when the plant is in flower. Stramonium leaf usually contains 0.2–0.45% of alkaloids, principally (−)-hyosycamine and (−)-hyoscine in a ratio of about 2:1. In young plants, (−)-hyoscine can predominate.

The generic name Datura is derived from dhat, an Indian poison used by the Thugs. The narcotic properties of Datura species, especially D. metel, have been known and valued in India for centuries. The plant material was usually absorbed by smoking. Most species of Datura contain similar tropane alkaloids and are potential sources of medicinal alkaloids. In particular, Datura sanguinea, a perennial of treelike stature with blood-red flowers, is cultivated in Ecuador, and yields leaf material with a high (0.8%) alkaloid content in which the principal component is (−)-hyoscine. The plants can be harvested several times a year. Datura sanguinea, and several other species of the tree-daturas (now classified as a separate genus Brugmansia) are widely cultivated as ornamentals, especially for conservatories, because of their attractive large tubular flowers. The toxic potential of these plants is not always recognized.

Hyosycamus

Hyoscyamus niger (Solanaceae), or henbane, is a European native with a long history as a medicinal plant. Its inclusion in mediaeval concoctions and its power to induce hallucinations with visions of flight may well have contributed to our imaginary view of witches on broomsticks. The plant has both annual and biennial forms, and is cultivated in Europe and North America for drug use, the tops being collected when the plant is in flower, and then dried rapidly. The alkaloid content of hyoscyamus is relatively low at 0.045–0.14%, but this can be composed of similar proportions of (−)-hyoscine and (−)-hyosycamine. Egyptian henbane, Hyosycamus muticus, has a much higher alkaloid content than H. niger, and although it has mainly been collected from the wild, especially from Egypt, it functions as a major commercial source for alkaloid production. Some commercial cultivation occurs in California. The alkaloid content of the leaf is from 0.35% to 1.4%, of which about 90% is (−)-hyoscyamine.

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Duboisia

Duboisia is a small genus of trees, containing only three species, found in Australia, again from the family Solanaceae. Two of these, Duboisia myoporoides and D. leichhardtii are grown commercially in Australia for tropane alkaloid production. The small trees are kept as bushes to allow frequent harvesting, with up to 70–80% of the leaves being removed every 7–8 months. The alkaloid content of the leaf is high, up to 3% has been recorded, and it includes (−)-hyoscyamine, (−)-hyoscine, and a number of related structures. The proportion of hyoscyamine to hyoscine varies according to the species used, and the area in which the trees are grown. The hyoscine content is frequently much higher than that of hyoscyamine. Indeed, interest in Duboisia was very much stimulated by the demand for hyoscine as a treatment for motion sickness in military personnel in the Second World War. Even higher levels of alkaloids, and higher proportions of hyoscine, can be obtained from selected D. myoporoides × D. leichhardtii hybrids, which are currently cultivated. The hybrid is superior to either parent, and can yield 1–2.5% hyoscine and 0–1% hyoscyamine. Duboisia leaf is an important commercial source of medicinal tropane alkaloids.

The third species of Duboisia, D. hopwoodi, contains little tropane alkaloid content, but produces mainly nicotine and related alkaloids, e.g. nornicotine (see page 313). Leaves of this plant were chewed by aborigines for their stimulating effects.

Allied Drugs

Tropane alkaloids, principally hyoscyamine and hyoscine, are also found in two other medicinal plants, scopolia and mandrake, but these plants find little current use. Scopolia (Scopolia carniolica; Solanaceae) resembles belladonna in appearance, though it is considerably smaller. Both root and leaf materials have been employed medicinally. The European mandrake (Mandragora officinarum; Solanaceae) has a complex history as a hypnotic, a general panacea, and an aphrodisiac. Its collection has been surrounded by much folklore and superstition, in that pulling it from the ground was said to drive its collector mad due to the unearthly shrieks emitted. The roots are frequently forked and are loosely likened to a man or woman. Despite the Doctrine of Signatures, which teaches that the appearance of an object indicates its special properties, from a pharmacological point of view, this plant would be much more efficient as a pain-reliever than as an aphrodisiac.

Hyoscyamine, Hyoscine and Atropine

All the above solanaceous plants contain as main alkaloidal constituents the tropane esters (−)-hyoscyamine and (−)-hyoscine, together with other minor tropane alkaloids. The piperidine ring in the bicyclic tropane system has a chairlike conformation, and there is a ready inversion of configuration at the nitrogen atom so that the N-methyl group can equilibrate between equatorial and axial positions (Figure 6.6). An equatorial methyl is strongly favoured provided there are no substituents on the two-carbon bridge, in which case the axial form may predominate. (−)-Hyoscyamine is the ester of tropine (Figure 6.4) with (−)- (S)-tropic acid, whilst (−)-hyoscine contains scopine (Figure 6.8) esterified with (−)-(S)-tropic acid. The optical activity of both hyoscyamine and hyoscine stems from the chiral centre

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Figure 6.9

natural laevorotatory form. These alkaloids compete with acetylcholine for the muscarinic site of the parasympathetic nervous system, thus preventing the passage of nerve impulses, and are classified as anticholinergics. Acetylcholine binds to two types of receptor site, described as muscarinic or nicotinic, from the specific triggering of a response by the Amanita muscaria alkaloid muscarine or the tobacco alkaloid nicotine (see page 314) respectively. The structural similarity between acetylcholine and muscarine (Figure 6.9) can readily be appreciated, and hyoscyamine is able to occupy the same receptor site by virtue of the spatial relationship between the nitrogen atom and the ester linkage (Figure 6.9). The side-chain also plays a role in the binding, explaining the difference in activities between the two enantiomeric forms. The agonist properties of hyoscyamine and hyoscine give rise to a number of useful effects, including antispasmodic action on the gastrointestinal tract, antisecretory effect controlling salivary secretions during surgical operations, and as mydriatics to dilate the pupil of the eye. Hyoscine has a depressant action on the central nervous system and finds particular use as a sedative to control motion sickness. One of the side-effects from oral administration of tropane alkaloids is dry mouth (the antisecretory effect) but this can be much reduced by transdermal administration. In motion sickness treatment, hyoscine can be supplied via an impregnated patch worn behind the ear. Hyoscine under its synonym scopolamine is also well known, especially in fiction, as a ‘truth drug’. This combination of sedation, lack of will, and amnesia was first employed in child-birth, giving what was termed ‘twilight sleep’, and may be compared with the mediaeval use of stramonium. The mydriatic use also has a very long history. Indeed, the specific name belladonna for deadly nightshade means ‘beautiful lady’ and refers to the practice of ladies at court who applied the juice of the fruit to the eyes, giving widely dilated pupils and a striking appearance, though at the expense of blurred vision through an inability to focus. Atropine also has useful antidote action in cases of poisoning caused by cholinesterase inhibitors, e.g. physostigmine and neostigmine (see page 366) and organophosphate insecticides.

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